Diisopropylethylamine → 4-(((3S,4S)-1-(2-cyano-2-methylpropanoyl)-4-ethylpyrrolidin-3-yl)amino)-6-(6-((2-methoxyacetamido)methyl)pyridin-3-yl)pyrrolo[1,2-b]pyridazine-3-carboxamide

HRID 877789Notes

Reaction equation

HRID 877789 reaction equation
[CH2:1]([C@H:3]1[CH2:7][NH:6][CH2:5][C@H:4]1[NH:8][C:9]1[C:10]2[N:11]([CH:18]=[C:19]([C:21]3[CH:22]=[N:23][C:24]([CH2:27][NH:28][C:29](=[O:33])[CH2:30][O:31][CH3:32])=[CH:25][CH:26]=3)[CH:20]=2)[N:12]=[CH:13][C:14]=1[C:15]([NH2:17])=[O:16])[CH3:2].[C:34]([C:36]([CH3:41])([CH3:40])[C:37](O)=[O:38])#[N:35].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:34]([C:36]([CH3:41])([CH3:40])[C:37]([N:6]1[CH2:7][C@H:3]([CH2:1][CH3:2])[C@H:4]([NH:8][C:9]2[C:10]3[N:11]([CH:18]=[C:19]([C:21]4[CH:22]=[N:23][C:24]([CH2:27][NH:28][C:29](=[O:33])[CH2:30][O:31][CH3:32])=[CH:25][CH:26]=4)[CH:20]=3)[N:12]=[CH:13][C:14]=2[C:15]([NH2:17])=[O:16])[CH2:5]1)=[O:38])#[N:35]

Participants

6

Reactant 4

HCID 81531DiisopropylethylamineHCID 151348Benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphateHCID 113670912-Cyano-2-methylpropanoic acidHCID 682914624-(((3S,4S)-4-ethylpyrrolidin-3-yl)amino)-6-(6-((2-methoxyacetamido)methyl)pyridin-3-yl)pyrrolo[1,2-b]pyridazine-3-carboxamide

Product 1

HCID 682911534-(((3S,4S)-1-(2-cyano-2-methylpropanoyl)-4-ethylpyrrolidin-3-yl)amino)-6-(6-((2-methoxyacetamido)methyl)pyridin-3-yl)pyrrolo[1,2-b]pyridazine-3-carboxamideYield 26%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

A mixture of 4-(((3S,4S)-4-ethylpyrrolidin-3-yl)amino)-6-(6-((2-methoxyacetamido)methyl)pyridin-3-yl)pyrrolo[1,2-b]pyridazine-3-carboxamide, 2hydroiodide (30 mg, 0.042 mmol), 2-cyano-2-methylpropanoic acid (14.39 mg, 0.127 mmol), BOP (56.3 mg, 0.127 mmol) and Hunig's Base (0.052 mL, 0.297 mmol) in DMF (0.25 mL) was stirred at rt for 2 hr. The reaction mixture was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×150 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 5-100% B over 15 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to afford the title compound (6 mg, 0.011 mmol, 26% yield). 1H NMR (500 MHz, METHANOL-d4) δ 8.79 (dd, J=9.4, 2.0 Hz, 1H), 8.14 (d, J=5.0 Hz, 1H), 8.06-7.93 (m, 2H), 7.38 (dd, J=8.2, 3.2 Hz, 1H), 7.20-7.10 (m, 1H), 5.07-4.87 (m, 1H), 4.57 (s, 2H), 4.36-4.14 (m, 2H), 3.97 (s, 2H), 3.95-3.68 (m, 2H), 3.46 (s, 3H), 2.68-2.44 (m, 1H), 1.83-1.39 (m, 8H), 1.07-0.95 (m, 3H). MS (ES+) m/z: 547.1 (M+H); LC retention time: 1.19 min (analytical LCMS Method H).

Workup

  1. customThe reaction mixture was purified via preparative LC/MS with the following conditions
  2. waitGradient: 5-100% B over 15 minutes
  3. customa 5-minute hold
  4. additionFractions containing the desired product
  5. customdried via centrifugal evaporation

Sources & evidence

ORD record
ord-61ba26bbf12545f48b170feae7e9ccc5
Source dataset
uspto-grants-2015_03
Patent number
US08987268B2

Reaction notes

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